Background: N6-methyladenosine (m6A) related long noncoding RNAs (lncRNAs) may have prognostic value in bladder cancer for their key role in tumorigenesis and innate immunity.Methods: Bladder cancer transcriptome data and the corresponding clinical data were acquired from the Cancer Genome Atlas (TCGA) database. The m6A-immune-related lncRNAs were identified using univariate cox regression analysis and Pearson correlation analysis. A risk model was established using least absolute shrinkage and selection operator (LASSO) Cox regression analyses, and analyzed using nomogram, time-dependent receiver operating characteristics (ROC) and Kaplan-Meier survival analysis. The differences in infiltration scores, clinical features, and sensitivity to Talazoparib of various immune cells between low- and high-risk groups were investigated. Findings: Totally 618 m6A-immune-related lncRNAs and 490 immune-related lncRNAs were identified from TCGA, and 47 lncRNAs of their intersection demonstrated prognostic values. A risk model with 11 lncRNAs was established by Lasso COX regression, and can predict the prognosis of bladder cancer patients as demonstrated by time-dependent ROC and Kaplan–Meier analysis. Significant correlations were determined between risk score and tumor malignancy or immune cell infiltration. Meanwhile, significant differences were observed in tumor mutation burden and stemness-score between the low-risk group and high-risk group. Moreover, high-risk group patients were more responsive to Talazoparib. Interpretation: An m6A-immune-related lncRNA risk model was established in this study, which can be applied to predict prognosis, immune landscape and chemotherapeutic response in bladder cancer.Keywords: m6A (N6-methyladenosine), long noncoding RNA, bladder cancer (BLCA), prognosis, immune microenvironment.Funding Information: This work was supported by grants from the National Natural Science Foundation of China (81902576, 81725016, 81872094, 81772718), Guangzhou Science and Technology Projects (202201010910), the China Postdoctoral Science Foundation Funded Project (2020M683082), and Guangdong Basic and Applied Basic Research Foundation (2020A1515010086).Declaration of Interests: The authors have no conflicts of interests.
Abstract Background: To investigate the value of contrast-enhanced transrectal ultrasound (CETRUS) in reducing unnecessary biopsy during prostate cancer screening and predicting biochemical recurrence in patients with localized prostate cancer. Methods:This was a prospective study of patients suspected of prostate cancer who were evaluated with CETRUS followed by prostate biopsy. Prostate blood flow on CETRUS was graded using a 5-point scale. The relationship between CETRUS score and biopsy outcomes was analyzed; Univariate and multi-variate analyses were used to determine the probable prognostic factors with biochemical recurrence in patients with localized prostate cancer underwent radical prostatectomy. Results:A total of 347 patients were enrolled. Prostate cancer was found in 164 patients. A significant positive correlation (r = 0.69, p < 0.001) was found between CETRUS scores and prostate cancer. Using CETRUS score ≥ 2 as the threshold for biopsy could have reduced the number of biopsies by 12.1% (42/347) without missing cancer and spared 23.0% (42/183) of patients from unnecessary biopsy. 77 patients with localized prostate cancer underwent radical prostatectomy and followed up. 17 of 77 patients exhibited biochemical recurrence. The 3-year biochemical recurrence-free survival rates were 86% for patients with CETRUS low scores (≤ 3) and 59% for patients with high scores (> 3; p = 0.015). Multivariate Cox regression analysis showed that CETRUS score was an independent predictor of biochemical recurrence (HR: 7.02; 95% CI: 2.00-24.69; p = 0.002). Conclusions:CETRUS score may be a useful tool to reduce unnecessary biopsy during prostate cancer screening and predict biochemical recurrence of localized prostate cancer after radical prostatectomy.
Abstract Background: To investigate the value of using contrast-enhanced transrectal ultrasound (CETRUS) to reduce unnecessary collection of biopsies during prostate cancer diagnosis and its utility in predicting biochemical recurrence in patients with localized prostate cancer. Methods: This was a prospective study of suspected prostate cancer patients who were evaluated with CETRUS followed by a prostate biopsy. Prostate blood flow via CETRUS was graded using a 5-point scale. The relationship between CETRUS score and biopsy outcome was then analyzed for all patients; univariate and multi-variate analyses were used to determine the probable prognostic factors for biochemical recurrence in patients with localized prostate cancer that underwent a radical prostatectomy. Results: A total of 347 patients were enrolled in the study. Prostate cancer was found in 164 patients. A significant positive correlation (r = 0.69, p < 0.001) was found between CETRUS scores and prostate cancer incidence. Using CETRUS scores ≥ 2 as the threshold for when to biopsy could have safely reduced the number of biopsies taken overall by 12.1% (42/347) and spared 23.0% (42/183) of patients from undergoing an unnecessary biopsy. 77 patients with localized prostate cancer underwent a radical prostatectomy. The median follow-up time was 30 months (range: 8-56 months) and 17 of these 77 patients exhibited biochemical recurrence during the follow-up period. 3-year biochemical recurrence-free survival rates were 86% for patients with low CETRUS scores (≤ 3) and 59% for patients with high scores (> 3; p = 0.015). Multivariate Cox regression analysis indicated that CETRUS score was an independent predictor of biochemical recurrence (HR: 7.02; 95% CI: 2.00-24.69; p = 0.002). Conclusions: CETRUS scores may be a useful tool for reducing the collection unnecessary biopsy samples during prostate cancer diagnosis and are predictive of biochemical recurrence in patients with localized prostate cancer following a radical prostatectomy.
Although neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) have been reported an 6% absolute improvement in 5-year overall survival (OS) for muscle invasive bladder cancer (MIBC), criticism still exists including the delay of surgery and the lack of accurate pathological evidence guidance. Trials have instead focused on adjuvant chemotherapy (AC) but encountered with many difficulties. Convincing data directly compared the treatment efficacy of these 2 strategies are lacking.We conducted a retrospective cohort study to compare the effectiveness of NAC versus AC among patients with T2-4N0-3M0 bladder cancer using the Surveillance, Epidemiology, and End Results (SEER) database. OS and cancer-specific survival (CSS) were compared using Kaplan-Meier (KM) survival estimators and univariate Cox proportional hazards regression models adjusted for inverse probability of treatment weighting (IPTW). The baseline between groups were compared using standardized mean differences (SMD) approach and kernel density plot. Sensitivity analysis was performed to test the robustness of our results.In total, 1,620 (38.9%) of all eligible patients (4,169) received NAC and 2,549 (61.1%) received AC. After adjusted for propensity score, all baseline characteristics were balanced with SMD <10%. The IPTW-adjusted survival analyses revealed no significant difference in OS between the 2 groups [adjusted hazard ratio (AHR) 1.09, 95% confidence interval (CI): 0.99-1.20, P=0.1]. Exploratory subgroup analysis indicated longer OS among lymph node-negative patients treated with NAC (AHR 1.25, 95% CI: 1.1-1.4, P=0.001), whereas lymph node-positive patients were in favor of AC (AHR 0.85, 95% CI: 0.72-0.99, P=0.043). This treatment heterogeneity according to lymph node status is associated with better prognosis in Stage II (T2N0) patients receiving NAC (AHR 1.28, 95% CI: 1.1-1.6, P=0.014). Meanwhile, in stage III-IV (T3-T4 and/or N+) diseases, NAC shares similar treatment efficacy to AC (AHR 0.98, 95% CI: 0.87-1.1, P=0.762). The analyses of CSS yielded similar, robust results on the effect of potential unmeasured confounding variables.Our population-based study suggests that NAC and AC might be interchangeable in MIBC management, especially in patients with Stage III-IV (T3-T4 and/or N+) diseases. However, this conclusion needs further validation from powerful, robust randomized trials.
Abstract Purpose There are undetectable levels of fat in fat-poor angiomyolipoma. Thus, it is often misdiagnosed as renal cell carcinoma. We aimed to develop and evaluate a multichannel deep learning model for differentiating fat-poor angiomyolipoma (fp-AML) from renal cell carcinoma (RCC). Methods This two-center retrospective study included 320 patients from the First Affiliated Hospital of Sun Yat-Sen University (FAHSYSU) and 132 patients from the Sun Yat-Sen University Cancer Center (SYSUCC). Data from patients at FAHSYSU were divided into a development dataset (n = 267) and a hold-out dataset (n = 53). The development dataset was used to obtain the optimal combination of CT modality and input channel. The hold-out dataset and SYSUCC dataset were used for independent internal and external validation, respectively. Results In the development phase, models trained on unenhanced CT images performed significantly better than those trained on enhanced CT images based on the fivefold cross-validation. The best patient-level performance, with an average area under the receiver operating characteristic curve (AUC) of 0.951 ± 0.026 (mean ± SD), was achieved using the “unenhanced CT and 7-channel” model, which was finally selected as the optimal model. In the independent internal and external validation, AUCs of 0.966 (95% CI 0.919–1.000) and 0.898 (95% CI 0.824–0.972), respectively, were obtained using the optimal model. In addition, the performance of this model was better on large tumors (≥ 40 mm) in both internal and external validation. Conclusion The promising results suggest that our multichannel deep learning classifier based on unenhanced whole-tumor CT images is a highly useful tool for differentiating fp-AML from RCC.
Abstract Background: Generally, both strands of a single pre-miRNA have been demonstrated to play a similar role in the same tumor type. However, there are no available literatures yet so far clarifying the opposite roles of both strands froma single miRNAin one tumor type. The purpose of this study is to investigate the functional role of both strands of miR-154 in bone metastasis of prostate cancer (PCa). Methods: miR-154-5p expression was examinedin 285 clinicalPCa tissuesby in situ hybridization. The clinical correlation ofmiR-154-5p expression with clinicopathological features,and overall and bone metastasis-free survival inPCa patients was evaluated by Kaplan-Meier survival and statisticalanalysis. The biological roles of miR-154-3p and miR-154-5p in the bone metastasis of PCa were investigated both in vitro and in vivo .Bioinformatics analysis, western blot and luciferase reporter analysis were used to determinethe potential targets of miR-154-5p.Luciferase assay and Western blotting were performed to clarify the underlying pathway implicated in the role of miR-154-5p in bone metastasis of PCa. Results: Contrary to the well established pro-bone metastatic role of miR-154-3p in PCa, we found that miR-154-5p expression was reduced in PCa tissues with bone metastasis andbone metastatic PCa cell lines. Downexpression of miR-154-5p was positively associated with bone metastasis status, and predicted poorer bone metastasis-free survival in PCa patients. Gain of function experiments showed that upregulating miR-154-5p repressed, while silencing miR-154-5p promoted invasion, migration and proliferation capacities of PCa cells in vitro . Conversely, miR-154-3p yielded an opposite effect oninvasion and migration capacities of PCa cells. Importantly, administration of agomir-154-5p effectivelyinhibited bone metastasis of PCa cells in vivo . Mechanistic dissection further demonstrated miR-154-5p inhibited invasion, migration and proliferation by targeting EGFR and FGFR1, leading to inactivation of PI3K/AKT signaling. However, the autocrine levels of corresponding ligands in the supernantant of PCa cells were not affected by the changed expression of miR-154-5p. Conclusion: Our results for the first time reveal the different role of both strands froma single miRNA in bone metastasis of PCa, which will facilitate the development of anti-bone metastatic therapeutic strategy in PCa.
Most localized human renal clear cell carcinoma (ccRCC)-related deaths result from cancer recurrence and metastasis. However, the precise molecular mechanisms largely remain unknown. In recent years, an increasing number of long noncoding RNAs (lncRNAs) have been shown to be vital regulators of tumorigenesis. In this study, we characterized a lncRNA DUXAP9 and the upregulation of DUXAP9 was analyzed by quantitative real-time PCR in 112 pairs of localized ccRCC tumor tissues compared with adjacent normal tissues. Kaplan–Meier curves showed that patients of localized ccRCC with high DUXAP9 expression had poorer overall survival (P<0.01) and progression-free survival (P<0.05) than cases with low DUXAP9 expression. Multivariate Cox regression analysis also showed that high DUXAP9 expression was an independent risk factor for poor prognosis in localized ccRCC (p<0.05). DUXAP9 knockdown in renal cancer cells inhibited renal cancer cells proliferation and motility capacities in vitro and reversed epithelial–mesenchymal transition (EMT), whereas overexpression of DUXAP9 promoted renal cancer cells proliferation and motility capacities in vitro and induced EMT. Pull-down, RNA immunoprecipitation and RNA stability assays (involving actinomycin D) showed that DUXAP9 was methylated at N6-adenosine and binds to IGF2BP2, which increases its stability. DUXAP9 activate PI3K/AKT pathway and Snail expression in renal cancer cells. DUXAP9 may be useful as a prognostic marker and/or therapeutic target in localized ccRCC.
Currently, immune checkpoint inhibitor (ICI)-based therapy has become the first-line treatment for advanced renal cell carcinoma (RCC). However, few biomarkers have been identified to predict the response to ICI therapy in RCC patients. Herein, our research aimed to build a gene mutation prognostic indicator for ICI therapy.This multi-cohort study explored the mutation patterns in 2 publicly available advanced RCC ICI therapy cohorts, the Memorial Sloan Kettering Cancer Center (MSKCC) advanced RCC ICI therapy cohort and the CheckMate ICI therapy cohort. A total of 261 patients in the CheckMate ICI therapy cohort were randomly assigned to either the training or validation set. Least absolute shrinkage and selection operator (Lasso) logistic regression analysis was subsequently used to develop a mutation classifier utilizing the training set. The classifier was then validated internally in the validation set and externally in 2 ICI therapy cohorts and 2 non-ICI therapy cohorts. Survival analysis, receiver operator characteristic curves and Harrell's concordance index were performed to assess the prognostic value of the classifier. Function and immune microenvironment analysis in each subgroup defined by the classifier were performed.A 10-gene mutation classifier was constructed based on the CheckMate ICI therapy cohort to separate patients into 2 risk groups, with patients in the high-risk group showing significantly lower overall survival probability than those in the low-risk group [the training set (HR: 1.791; 95% CI: 1.207-2.657; P=0.003), the validation set (HR: 1.842; 95% CI: 1.133-2.996; P=0.012) and combination set (HR: 1.819; 95% CI: 1.339-2.470; P<0.001)]. Further validation confirmed that the mutation classifier only showed predictive value for patients receiving ICI therapy instead of non-ICI therapy. Combined with the clinical characteristics, the risk score was proven to be an independent prognostic factor for overall survival in ICI therapy by multivariate Cox regression analysis. Functional and immune infiltration analysis demonstrated that lower risk scores tended to associate with immunologically "hot" status in RCC.Our 10-gene mutation classifier was found to be a biomarker for predicting the overall survival of patients with advanced RCC to ICI therapy.
Objectives To evaluate the perioperative condition and clinical effect in retroperitoneal laparoscopic partial nephrectomy(RLPN) for early-stage renal carcinoma.Methods The clinical date of 36 patients who underwent retroperitoneal laparoscopic partial nephrectomy were retrospectively compared with those of 38 patients who underwent open partial nephrectomy (OPN) for early-stage renal carcinoma,including mean operation time,warm ischemia time,mean estimated blood loss,postoperative drainage volume,blood transfusion rate,resumption of oral intake,postoperative hospital stay and complications incidence from January 2008 to December 2012.Results There were no significant difference in sex,age,tumor size and preoperative renal function in two groups.The mean operation time of two groups was (142.67 ±41.26) mins and(128.33 ± 32.27) mins,the warm ischemia time was (29.68 ± 4.92) mins and (24.85 ± 3.66) mins.RLPN group showed a bit longer than OPN group.The mean estimated blood loss of two groups was (138.25 ± 48.13) ml and (236.67 ±82.37)ml,the postoperative drainage volume was (88.96 ±25.37)ml and (126.56 ±33.29)ml,the resumption of oral intake was (2.21 ±0.49)d and (3.32 ±0.61)d,the postoperative hospital stay was (7.28 ± 1.47)d and (9.39 ± 1.70)d,RLPN group was superior in these statistical variables to OPN group(P ＜ 0.05).The complications incidence of two groups was 13.9％ (5/36) and 13.2％ (5/38) and it shows no significant difference(P ＞0.05).Conclusions RLPN is comparably safe as OPN,and takes obvious advantage in minimally invasive surgery with well clinical effects,and would be a safe and reliable surgery treatment for early-stage renal carcinoma.
Key words:
Kidney Neoplasms ; Nephrectomy ; Laparoscopy
Clear cell renal cell carcinoma (ccRCC) is a highly invasive and metastatic subtype of kidney malignancy and is correlated with metabolic reprogramming for adaptation to the tumor microenvironment comprising infiltrated immune cells and immunomodulatory molecules. The role of immune cells in the tumor microenvironment (TME) and their association with abnormal fatty acids metabolism in ccRCC remains poorly understood. RNA-seq and clinical data of KIRC from The Cancer Genome Atlas (TCGA) and E-MTAB-1980 from the ArrayExpress dataset. The Nivolumab group and Everolimus group of the CheckMate 025 study, the Atezolizumab arm of IMmotion150 and the Atezolizumab plus Bevacizumab group of IMmotion151 cohort were obtained for subsequent analysis. After differential expression genes identification, the signature was constructed through univariate Cox proportional hazard regression and simultaneously the least absolute shrinkage and selection operator (Lasso) analysis and the predictive performance of our signature was assessed by using receiver operating characteristic (ROC), Kaplan-Meier (KM) survival analysis, nomogram, drug sensitivity analysis, immunotherapeutic effect analysis and enrichment analysis. Immunohistochemistry (IHC), qPCR and western blot were performed to measure related mRNA or protein expression. Biological features were evaluated by wound healing, cell migration and invasion assays and colony formation test and analyzed using coculture assay and flow cytometry. Twenty fatty acids metabolism-related mRNA signatures were constructed in TCGA and possessed a strong predictive performance demonstrated through time-dependent ROC and KM survival analysis. Notably, the high-risk group exhibited an impaired response to anti-PD-1/PD-L1 (Programmed death-1 receptor/Programmed death-1 receptor-ligand) therapy compared to the low-risk group. The overall levels of the immune score were higher in the high-risk group. Additionally, drug sensitivity analysis observed that the model could effectively predict efficacy and sensitivity to chemotherapy. Enrichment analysis revealed that the IL6-JAK-STAT3 signaling pathway was a major pathway. IL4I1 could promote ccRCC cells' malignant features through JAK1/STAT3 signaling pathway and M2-like macrophage polarization. The study elucidates that targeting fatty acids metabolism can affect the therapeutic effect of PD-1/PD-L1 in TME and related signal pathways. The model can effectively predict the response to several treatment options, underscoring its potential clinical utility.
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